美国斯坦福大学Crystal L. Mackall研究团队发现，蛋白酶调控的CAR-T细胞受体可增强安全性和有效性。2022年4月27日，国际知名学术期刊《细胞》在线发表了这一成果。
研究人员提出了SNIP CAR，一个基于蛋白酶的平台，使用FDA批准的小分子来调节CAR的活性。设计迭代产生的CAR-T细胞，在有药物的情况下表现出完全的功能能力，而在没有药物的情况下没有泄漏的活性。在许多模型中，SNIP CAR-T细胞比组成型CAR-T细胞更有效，并显示出T细胞衰竭的减少和更大的干性。在一个基于ROR1的CAR致死模型中，在毒性发生后停止用药可逆转毒性，从而使该平台成为一个安全开关的凭证。
在同一模型中，减少药物剂量打开了一个治疗窗口，导致肿瘤在没有毒性的情况下被根除。SNIP CAR实现了CAR活性的远程调整，这为目前限制使用CAR-T细胞治疗实体瘤的安全和疗效障碍提供了解决方案。
据悉，可调控的CAR平台可以规避与CAR-T疗法相关的毒性，但现有的系统有缺陷，包括泄漏和减弱的活性。
附：英文原文
Title: Enhanced safety and efficacy of protease-regulated CAR-T cell receptors
Author: Louai Labanieh, Robbie G. Majzner, Dorota Klysz, Elena Sotillo, Chris J. Fisher, José G. Vilches-Moure, Kaithlen Zen B. Pacheco, Meena Malipatlolla, Peng Xu, Jessica H. Hui, Tara Murty, Johanna Theruvath, Nishant Mehta, Sean A. Yamada-Hunter, Evan W. Weber, Sabine Heitzeneder, Kevin R. Parker, Ansuman T. Satpathy, Howard Y. Chang, Michael Z. Lin, Jennifer R. Cochran, Crystal L. Mackall
Issue&Volume: 2022-04-27
Abstract: Regulatable CAR platforms could circumvent toxicities associated with CAR-T therapy, but existing systems have shortcomings including leakiness and attenuated activity. Here, we present SNIP CARs, a protease-based platform for regulating CAR activity using an FDA-approved small molecule. Design iterations yielded CAR-T cells that manifest full functional capacity with drug and no leaky activity in the absence of drug. In numerous models, SNIP CAR-T cells were more potent than constitutive CAR-T cells and showed diminished T cell exhaustion and greater stemness. In a ROR1-based CAR lethality model, drug cessation following toxicity onset reversed toxicity, thereby credentialing the platform as a safety switch. In the same model, reduced drug dosing opened a therapeutic window that resulted in tumor eradication in the absence of toxicity. SNIP CARs enable remote tuning of CAR activity, which provides solutions to safety and efficacy barriers that are currently limiting progress in using CAR-T cells to treat solid tumors.
DOI: 10.1016/j.cell.2022.03.041
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00391-9